A unifying statistical framework to discover disease genes from GWASs.

Genome-wide association studies (GWASs) identify genomic loci associated with complex traits, but it remains a challenge to identify the genes affected by causal genetic variants in these loci. Attempts to solve this challenge are frustrated by a number of compounding problems. Here, we show how to combine solutions to these problems into a unified mathematical framework. From this synthesis, it becomes possible to compute the probability that each gene in the genome is affected by a causal variant, given a particular trait, without making assumptions about the relevant cell types or tissues. We validate each component of the framework individually and in combination. When applied to large GWASs of human disease, the resulting paradigm can rediscover the majority of well-known disease genes. Moreover, it establishes human genetics support for many genes previously implicated only by clinical or preclinical evidence, and it uncovers a plethora of novel disease genes with compelling biological rationale.

Adult cortical plasticity studied with chronically implanted electrode arrays.

The functional architecture of adult cerebral cortex retains a capacity for experience-dependent change. This is seen after focal binocular lesions as rapid changes in receptive field (RF) of the lesion projection zone (LPZ) in the primary visual cortex (V1). To study the dynamics of the circuitry underlying these changes longitudinally, we implanted microelectrode arrays in macaque (Macaca mulatta) V1, eliminating the possibility of sampling bias, which was a concern in previous studies. With this method, we observed a rapid initial recovery in the LPZ and, during the following weeks, 63-89% of the sites in the LPZ showed recovery of visual responses with significant position tuning. The RFs shifted ∼3° away from the scotoma. In the absence of a lesion, visual stimulation surrounding an artificial scotoma did not elicit visual responses, suggesting that the postlesion RF shifts resulted from cortical reorganization. Interestingly, although both spikes and LFPs gave consistent prelesion position tuning, only spikes reflected the postlesion remapping.

Top-down modulation of lateral interactions in visual cortex.

The primary visual cortex (V1) changes its computation according to the perceptual task being performed. We propose that this cognitive modulation results from gating of V1 intrinsic connections. To test this idea, using behavioral paradigms that engage top-down modulation of V1 contextual interactions, we recorded from chronically implanted electrode arrays in macaques. We observed task-dependent changes in interactions between V1 sites measured both by correlation between spike trains and by coherence between local field potentials (LFP-LFP coherence). The direction of the changes in aggregate activity, as measured by LFPs, depended on perceptual strategy: perceptual grouping increased LFP coherence between sites crucial for the task, whereas perceptual segregation lowered the LFP coherence. Using spiking activity as a measure, we found that the behaviorally driven changes in correlation structure between neurons dramatically increased the stimulus-related information that they convey; this additional increase in encoded information at the level of neuronal ensembles equals that obtained from task-driven reconfigurations of neural tuning curves. The improvements in information encoding were strongest for stimuli with greatest discrimination difficulty.

Adaptive shape processing in primary visual cortex.

The ability to derive meaning from complex sensory input requires the integration of information over space and time, as well as cognitive mechanisms to shape that integration. We studied these processes in the primary visual cortex (V1), where neurons are thought to integrate visual inputs along contours defined by an association field (AF). We recorded extracellularly from single cells in macaque V1 to map the AF, by using an optimization algorithm to find the contours that maximally activated individual cells. We combined the algorithm with a delayed-match-to-sample task, to test how the optimal contours might be molded by the monkey's expectation for particular cue shapes. We found that V1 neurons were selective for complex shapes, a property previously ascribed to higher cortical areas. Furthermore, the shape selectivity was reprogrammed by perceptual task: Over the whole network, the optimal modes of geometric selectivity shifted between distinct subsets of the AF, alternately representing different stimulus features known to predominate in natural scenes. Our results suggest a general model of cortical function, whereby horizontal connections provide a broad domain of potential associations, and top-down inputs dynamically gate these linkages to task switch the function of a network.

Axonal dynamics of excitatory and inhibitory neurons in somatosensory cortex.

Cortical topography can be remapped as a consequence of sensory deprivation, suggesting that cortical circuits are continually modified by experience. To see the effect of altered sensory experience on specific components of cortical circuits, we imaged neurons, labeled with a genetically modified adeno-associated virus, in the intact mouse somatosensory cortex before and after whisker plucking. Following whisker plucking we observed massive and rapid reorganization of the axons of both excitatory and inhibitory neurons, accompanied by a transient increase in bouton density. For horizontally projecting axons of excitatory neurons there was a net increase in axonal projections from the non-deprived whisker barrel columns into the deprived barrel columns. The axon collaterals of inhibitory neurons located in the deprived whisker barrel columns retracted in the vicinity of their somata and sprouted long-range projections beyond their normal reach towards the non-deprived whisker barrel columns. These results suggest that alterations in the balance of excitation and inhibition in deprived and non-deprived barrel columns underlie the topographic remapping associated with sensory deprivation.

Rapid axonal sprouting and pruning accompany functional reorganization in primary visual cortex.

The functional architecture of adult cerebral cortex retains a capacity for experience-dependent change. This is seen following focal binocular lesions, which induce rapid changes in receptive field size and position. To follow the dynamics of the circuitry underlying these changes, we imaged the intrinsic long-range horizontal connections within the lesion projection zone (LPZ) in adult macaque primary visual cortex. To image the same axons over time, we combined viral vector-mediated EGFP transfer and two-photon microscopy. The lesion triggered, within the first week, an approximately 2-fold outgrowth of axons toward the center of the LPZ. Over the subsequent month, axonal density declined due to a parallel process of pruning and sprouting but maintained a net increase relative to prelesion levels. The rate of turnover of axonal boutons also increased. The axonal restructuring recapitulates the pattern of exuberance and pruning seen in early development and correlates well with the functional changes following retinal lesions.

A computational model of perceptual fill-in following retinal degeneration.

The ablation of afferent input results in the reorganization of sensory and motor cortices. In the primary visual cortex (V1), binocular retinal lesions deprive a corresponding cortical region [lesion projection zone (LPZ)] of visual input. Nevertheless, neurons in the LPZ regain responsiveness by shifting their receptive fields (RFs) outside the retinal lesions; this re-emergence of neural activity is paralleled by the perceptual completion of disrupted visual input in human subjects with retinal damage. To determine whether V1 reorganization can account for perceptual fill-in, we developed a neural network model that simulates the cortical remapping in V1. The model shows that RF shifts mediated by the plexus of spatial- and orientation-dependent horizontal connections in V1 can engender filling-in that is both robust and consistent with psychophysical reports of perceptual completion. Our model suggests that V1 reorganization may underlie perceptual fill-in, and it predicts spatial relationships between the original and remapped RFs that can be tested experimentally. More generally, it provides a general explanation for adaptive functional changes following CNS lesions, based on the recruitment of existing cortical connections that are involved in normal integrative mechanisms.